Project summary The nervous system and neurotransmitters can significantly effect the function of the immune system. Recently, we have identified a novel CD4+ T-cell population that regulates innate immune function preventing mortality during septic shock. These unique T-cells exert regulatory function through production and release of the neurotransmitter of acetylcholine, inhibiting NF-?B dependent gene transcription in splenic macrophages. Release of this immuno-modulatory molecule is evoked by neurons that innervate the spleen, and release the neurotransmitter norepinephrine. Originally proposed to originate in the celiac ganglia, the anatomic origin of this splenic innervation has become highly controversial. The overall goals of this project are to refine the functional circuitry of communication between the nervous and immune systems. This will be achieved with mapping the origin of splenic sympathetic innervation using optogenetic stimulation of target ganglia with monitoring in target immune organs. Completion of these studies will yield important information in the basic immunological function of neuro-immune communication, providing a foundation for development of therapeutic devices.